tbuckley/cabot-search huggingface dataset:
NIMG-61. IMPROVED GENERALIZABILITY OF RADIOPATHOMIC PROBABILISTIC MAPPING OF TREATMENT-INDUCED EFFECTS WITH PHYSIOLOGIC MR IMAGING AND DEEP LEARNING IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Jacob Ellison, Nate Tran, Annette Molinaro, Valentina Pedoia, Joanna J Phillips, Anny Shai, Devika Nair, Marisa Lafontaine, Angela Jakary, Tracy Luks, Javier Villanueva-Meyer, Susan M Chang, Mitchel S Berger, Shawn L Hervey-Jumper, Manish Aghi, Janine Lupo
Journal: Neuro-Oncology (2022)

Abstract Although physiologic (diffusion-weighted and perfusion-weighted) MRI has shown promise in identifying regions of recurrent tumor (rTumor) in patients with glioblastoma suspected of progression, distinguishing treatment-induced effects (TxE) from rTumor on anatomical MRI remains a challenge. Whereas prior larger-scale machine learning (ML)-based studies mostly utilize anatomical imaging alone and/or perform lesion-level predictions, this study aimed to develop a non-invasive, radiopathomic tool for regional probabilistic mapping of TxE using 208 tissue-samples (55 pathologically-confirmed TxE, 153 recurrent glioblastoma) acquired from 107 patients with known spatial coordinates on pre-surgical MRI. We tested the hypothesis that applying a deep-learning (DL) model that included physiological MRI can: 1) more accurately identify areas of TxE that mimic rTumor on anatomical MRI and 2) better generalize to an independent test set than ML-models or a DL-model that uses anatomical MRI alone. An 80/20 split for training/validation was used after 1/3 of the patients were withheld for testing. Oversampling of TxE samples was employed to address class imbalance and an equal proportion of TxE samples was maintained across all datasets. Three ML-models, their ensemble, and a deep 4D-convolutional-neural-network were trained based on normalized anatomical (post-contrast T1, T2-FLAIR), diffusion-weighted (ADC, FA), and DSC perfusion-weighted (PeakHeight, %recovery) images cropped to 10mm-cubic patches centered on the coordinates from where tissue was obtained. Although Random Forest and voting-ensembled ML-models using all imaging and the anatomical DL-model had the best validation performance (AUC=0.81-0.82), these models did not generalize (test AUC=0.58-0.59). The DL-model including physiologic images had slightly lower validation AUC (0.78) but the best overall test AUC (0.795), indicating superior generalizability. Elevated blood volume (nPeakHeight) was the most important feature. Our DL-model’s interpretability was also demonstrated by disrupting class separation after shuffling voxels within each input patch. These results suggest that using deep-learning with physiologic MRI can improve intratumoral classification of TxE from rTumor.
EXTH-62. EXAMINATION OF THE TUMOR MICROENVIRONMENT OF GLIOMAS TREATED WITH VIROIMMUNOTHERAPY REVEALS THE PRODUCTION OF ONCOMETABOLITES LEADING TO IMPROVED THERAPEUTIC STRATEGIES
Authors: Teresa Nguyen, Dong Ho Shin, Debora Kim, Sanjay K Singh, Hong Jiang, Xuejun Fan, Yanhua Yi, Joy Gumin, Frederick Lang, Christopher Alvarez-Breckenridge, Marta M Alonso, Lijie Zhai, Erik Ladomersky, Kristen Lauing, Derek Wainwright, Juan Fueyo, Candelaria Gomez-Manzano
Journal: Neuro-Oncology (2022)

Abstract Oncolytic viruses are considered part of immunotherapy and have shown promise in preclinical experiments and clinical trials in a small fraction of patients. To improve the response rate, it is necessary to reshape the tumor microenvironment that shields the tumor from the immune system of the patient. We engineered Delta-24-RGDOX (DNX-2440), an oncolytic adenovirus to express the T-cell activator OX40L, which triggered, in murine glioblastoma models, a dramatic reshaping of the tumor microenvironment dominated by changes in immune processes in an RNA-seq analysis of ingenuity pathways. Paradoxically, network analyses also revealed that Delta-24-RGDOX induced robust activation of the cytokine-driven immunosuppressive IDO-Kynurenine-AhR circuitry, indicating a potential mechanism of resistance of gliomas to oncolytic virotherapy. To reverse this immunosuppression, we combined Delta-24-RGDOX with clinically relevant IDO inhibitors to treat glioma-bearing mice. The combined therapy decreased the activation of the IDO network without affecting viral activity. Flow cytometry assays revealed a decrease in the presence of the immunosuppressive cell populations, MDSCs and Tregs, which presence was higher in Delta-24-RGDOX-treated tumors. These data were further confirmed in gene set enrichment analyses. Functional co-culture studies showed that the combined therapy activated splenocytes against tumor antigens and that this activation was reversed by Kynurenine. Importantly, the combination treatment eradicated the tumors in a CD4-dependent manner and significantly prolonged the survival of glioma-bearing mice. Altogether, these studies indicate that the combination treatment promotes an adaptive immune response while decreasing the immunosuppression caused by the virus-induced IDO activation. Furthermore, our data identified the striking role of immunosuppressive pathways in the resistance of gliomas to oncolytic virotherapy. Specifically, the activity of the tumor microenvironment IDO circuitry was responsible, at least partially, for the remodeling of local immunosuppression after tumor infection. Combining molecular and immune-related therapies may improve outcomes in human gliomas treated with virotherapy.
IMMU-17. LEVERAGING CORE EPIGENETIC PROGRAMMING OF IMMUNOSUPPRESSIVE MYELOID CELLS FOR THERAPEUTIC TARGETING OF GLIOBLASTOMA
Authors: Defne Bayik, Cynthia Bartels, Katreya Lovrenert, Duo Zhang, Dionysios Watson, Kristen Kay, Juyeun Lee, Michael Vogelbaum, Yi Fan, Peter Scacheri, Justin Lathia
Journal: Neuro-Oncology (2022)

Abstract Accumulation of various immunosuppressive myeloid cells, including myeloid-derived suppressor cells (MDSCs), facilitates progression and treatment resistance of glioblastoma (GBM). We previous demonstrated that monocytic MDSCs (mMDSCs) but not granulocytic MDSCs (gMDSCs) infiltrate tumors in mouse models and patients, and that nonspecific targeting of mMDSCs with chemotherapies provided therapeutic benefit in preclinical models of GBM. To investigate the differential role and trafficking of mMDSCs versus gMDSCs in GBM, we adoptively transferred these cells into tumor-bearing mice. Mice that received mMDSCs succumbed to disease at an earlier point compared to control mice or mice that received gMDSCs. To delineate the cellular basis of this distinct behavior of MDSC subsets, we performed assay for transposase-accessible chromatin using sequencing (ATAC-seq) and observed that cell adhesion-related genes were significantly enriched in open chromatin regions of mMDSCs as opposed to gMDSCs. Aligned with this epigenetic profile, mMDSCs from blood and tumors had significantly higher surface integrin β1 expression compared to gMDSCs in both mouse models and GBM patients. To evaluate the functional role of these integrins, we pre-treated mMDSCs with anti-integrin β1 prior to adoptive transfer. Blockade of surface integrin β1 interfered with the pro-tumorigenic role of mMDSCs, as the survival span of mice receiving these cells was similar to that of vehicle controls. Further analysis of the ATAC-Seq data revealed that dipeptidyl peptidase-4 (Dpp4), an interacting partner of integrin β1, was more accessible in mMDSCs compared to gMDSC. Consistently, bone marrow-derived mMDSCs in mouse and tumor-infiltrating mMDSCs in GBM patients expressed high levels of Dpp4. Pharmacological inhibition of Dpp4 reduced chemotaxis of mMDSCs in vitro and extended survival duration of mice with tumors. The findings from this study have broad implications across cancer types to modulate immunosuppressive myeloid cells by leveraging these novel insights into their adhesion mechanisms.
DISP-13. FEMALE MICE HAVE GREATER SUSTAINED ACTIVITY SUPPRESSION AND HYPERSOMNOLENCE AFTER RADIATION THERAPY: EXPLORATION OF SEX DIFFERENCES IN A MODEL OF CRANIAL-RADIATION-INDUCED HYPERSOMNOLENCE (C-RIH)
Authors: Kendra Adegbesan, Francesco Tomassoni Ardori, Sudhirkumar Yanpallewar, Sean Bradley, Yogita Chudasama, Nicole Briceno, Amanda King, Lino Tessarollo, Mark Gilbert, DeeDee Smart, Terri Armstrong, Dorela Shuboni-Mulligan
Journal: Neuro-Oncology (2022)

Abstract Female cancer patients have a better prognosis but more adverse events with chemotherapy; less is known with other cancer treatments like radiation therapy. Previous literature has demonstrated sex-dependent effects on the hippocampi and behavioral tasks within post-natal mice after radiotherapy. We explored the differences in activity and sleep in adult male and female mice within our previously established mouse model of cranial-irradiation-induced hypersomnolence (C-RIH). Ten mice of each sex (B6 x B6D2 backcrossed with C57/b6NCr) were observed for general activity and sleep continuously over 10 days before and after therapeutic irradiation (whole brain, 15Gy, single fraction). Behavioral assessments aimed at measuring anxiety (Light Dark Box, Elevated Zero Maze) and depression (Sucrose Preference Test) related behaviors, and working memory (Y Maze) were then used to assess any radiation-induced changes in mood or cognition. Independent samples t-tests compared male and female cohorts before and after radiation. At baseline, females had significantly higher peak activity (p &amp;lt; 0.001), as well as day (p &amp;lt; 0.001), and night (p = 0.004) activity. Females also showed less anxiety in the Elevated Zero Maze (p &amp;lt; 0.001) and Light-Dark Box (p = 0.012). In the Y-Maze, females had significantly more alternations (entry into each arm without repeat) (p = 0.004). Males and females consumed the same proportion of sucrose solution in respect to water (p = 0.124). After radiation, males and females showed a significant decrease in activity, with females displaying a higher suppression of night activity both 1-3 days (t(18) = 2.162, p = 0.045) and 7-9 days (t(18) = 2.266, p = 0.037). Female mice also showed increased night hypersomnolence at 1-3 days (t(18) = 4.474, &amp;lt; p = 0.001) and 7-9 days (t(18) = 2.920, p = 0.01). Further analysis is underway on post-radiation sex differences in sleep and activity. Here we used a mouse model of C-RIH to assess the behavioral outcomes between the sexes and found marked effects on sleep and activity.
NCOG-15. A PILOT STUDY ON RETINAL FEATURES AND COGNITIVE FUNCTION IN PATIENTS WITH LOW GRADE GLIOMAS
Authors: Yin Allison Liu, Orwa Aboud, Megan Daly, Orin Bloch, Glenn Yiu
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Retinal structure and vascular changes are used as biomarkers for preclinical Alzheimer disease. We conducted a cohort study to evaluate the feasibility of obtaining these data in patients with low-grade gliomas (LGGs) who completed chemoradiation therapy with and without self or family reported cognitive concerns. METHODS Optical coherence tomography (OCT) and angiography (OCTA, OptoVue, Inc.) images were obtained from 6 LGG patients and 2 healthy controls using 4.5 x 4.5 mm peripapillary and 6x6 mm macular scan patterns. We measured OCTA parameters including radial peripapillary capillary density for the peri-optic disc region, whole macular density, and foveal avascular zone (FAZ). RESULTS We analyzed two eyes of two control subjects, an LGG patient with normal cognition, and 5 LGG patients with cognitive impairment (mean age 45 years, range of 3 months to 10 years after chemoradiation). Both controls had normal eye exams. Average retinal nerve fiber layer thickness was thinner in patients with and without cognitive dysfunction (104 um and 106 um, respectively) than controls (123 um). A similar pattern was seen in macula thickness (283 um and 290 um vs. 325 um). The average peripapillary vessel densities were lower in patients with and without cognitive dysfunction (47.7% and 48.3%, respectively) than controls (51.9%). The whole macular vessel densities were similar in three groups (46.7 %, 48.0%, and 48.0 %). Average FAZs were larger in patients with cognitive dysfunction (0.254 mm2) than the patient with normal cognition (0.204 mm2) and controls (0.226 mm2). CONCLUSIONS Retinal architecture and microvascular changes measured by OCT/OCTA is feasible in LGG patients after chemoradiation. A larger prospective study is needed to investigate the role of OCT/OCTA in detecting peripapillary and perifoveal changes in brain tumor patients with treatment-associated cognitive dysfunction.
NCOG-47. SYMPTOMATOLOGY OF PRIMARY BRAIN TUMOR PATIENTS AT CLINICAL TRIAL INITIATION: SNAPSHOT FROM THE NCI NOB-NATURAL HISTORY STUDY
Authors: Elizabeth Vera, Marta Penas-Prado, Brett Theeler, Jing Wu, Mark Gilbert, Terri Armstrong
Journal: Neuro-Oncology (2022)

Abstract Clinical trial endpoints include response/survival, but also treatment tolerance and clinical benefit. Few reports exist on the frequency and type of disease-related symptoms and functions and treatment-associated symptomatic toxicities at clinical trial initiation. The MD Anderson Symptom Inventory-Brain Tumor self-reports from patients at baseline of a clinical trial initiation were retrospectively evaluated for the presence of severe ratings ( ≥ 7 for symptom, ≥ 6 for interference) of Reeve's toxicity symptoms (TS) (pain, fatigue, nausea, insomnia, anxiety, dyspnea, anorexia, depression, vomiting, neuropathy, constipation, diarrhea) and RANO-COA Collaborative core disease-related symptoms (DRS) (pain, perceived cognition, difficulty communicating, seizure, physical function, role/social functioning). A total of 137 baseline assessments from 132 patients for 10 clinical trials were evaluated. Patients were primarily white (82%) males (67%), with median age 48 years (range: 19-76), initiating treatment for a recurrent (86%) high grade (95%) tumor. Thirty-six percent reported severe TS (range: 1-9) and 48% reported DRS (range: 1-8), both with a median of 2 symptoms. All 12 TS and 7 DRS were reported as severe (TS range: 3%-23%); DRS range: 1%-25%); most common were fatigue (23%), insomnia (12%), and anxiety (10%) for TS, and role/social function-work (25%), physical function-walking (24%), and role/social function-usual activity (20%) for DRS. Those ≤ 4 weeks since recurrence more frequently reported TS (53%) or DRS (62%). TS were more common if treatment initiation closely followed a previous treatment (0-4 weeks: 45%). Baseline symptom occurrence and functional limitations and their severity at clinical trial initiation are critical to understanding tolerability and clinical benefit. For TS, baseline adjustments are warranted for anticipated symptomatic toxicities. High disease-related symptom severity necessitates symptom management and supportive care approaches for patients entering clinical trials and promotes symptomatic improvement measures as trial endpoints along with traditional measures such as tumor reduction and prolongation of survival outcomes.
EXTH-14. INHIBITION OF THE ANGIOTENSIN II TYPE 2 RECEPTOR AT2R IS A NOVEL THERAPEUTIC STRATEGY FOR GLIOBLASTOMA
Authors: Richard Perryman, Alexander Renziehausen, Hamidreza Shaye, Androniki Kostagianni, Antonis Tsiailanis, Tom Thorne, Maria Chatziathanasiadou, Gregory Sivolapenko, Mohamed Ahmed El Mubarak, Gye Won Han, Barbara Zarzycka, Vsevolod Katritch, Guillaume Lebon, Cristiana Lo Nigro, Laura Lattanzio, Sophie Morse, James Choi, Kevin O’Neill, Zoe Kanaki, Apostolos Klinakis, Tim Crook, Vadim Cherezov, Andreas Tzakos, Nelofer Syed
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) is a primary malignant brain tumor with poor clinical outcomes. Standard of care consists of surgical debulking followed by radiation and temozolomide, but the tumor invariably recurs, and median survival is only ~18 months. Repurposing drugs used for the treatment of other diseases is a promising avenue to identify novel treatments for this highly aggressive form of cancer. One such class of compounds is angiotensin II (AngII) receptor blockers, commonly used to control blood pressure. We show that ~80% of primary human GBM express the angiotensin II type 2 receptor (AT2R). In the presence of AngII, inhibition of AT2R using either PD123319 or EMA401 significantly inhibits GBM proliferation. This effect was lost in GBM cells with CRISPR/Cas9 mediated knockdown of AT2R. EMA401 inhibited invasion, angiogenesis, reduced GBM spheroid growth and induced apoptosis through caspase 3/7 activation. Furthermore, EMA401 induced changes in a number of growth regulatory pathways including apoptosis, DNA replication and focal adhesion. The crystal structure of AT2R bound to EMA401 revealed the receptor to be in an active-like conformation with helix-VIII blocking G protein or β-arrestin recruitment. We demonstrate that the architecture and interaction of EMA401 with AT2R differs drastically from complexes of AT2R with other compounds. Conjugation of EMA401 to angiopep-2 enhanced its blood brain barrier passage and reduced tumor volume in an orthotopic xenograft model of GBM. Targeting AT2R is a novel therapeutic strategy to treat GBM that should be explored in patients.
TMIC-08. FRIEND AND FOE: RADIATION THERAPY MODULATES GLIOBLASTOMA IMMUNE EVASION VIA EXTRACELLULAR VESICLES
Authors: Markus Schweiger, Zohreh Amoozgar, Bakhos Tannous
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) is the most common form of malignant primary brain tumor and despite optimal treatment, long-term survival remains incredibly rare. Radiation therapy (RT) leads to successful initial tumor regression but recurrence is inevitable. Previous studies have shown that ionizing radiation changes the composition of the tumor microenvironment and alters the expression of immune-related markers on tumor cells. Extracellular vesicles (EVs) are vesicular bodies of cellular origin and secreted by nearly every cell. They have been shown to carry a variety of cargo (DNA, proteins, RNAs, lipids) which can be taken up by other cells. Notably, previous studies highlight that EVs drive GBM progression and immune evasion by acting as multifunctional signaling complexes. Here we show that ionizing radiation of GBM cells results in an altered EV secretome and further facilitates the uptake of EVs in recipient cells. In addition, EVs secreted by GBM cells following radiation modulate the tumor microenvironment by manipulating the innate as well as the adaptive immune response. Macrophages exposed to EVs from irradiated GBM cells switched to the tumor supportive M2 phenotype and exhibited decreased phagocytotic ability.We dissected a novel mechanism by which GBM evades the immune system with the help of EVs following RT, pointing towards novel therapeutic strategies to prevent GB recurrence.
NIMG-91. DOTATATE PET/MR-GUIDED POSTOPERATIVE MANAGEMENT IN WHO-2 MENINGIOMA: ACTIVE SURVEILLANCE BASED ON PET/MR EVIDENCE OF GROSS TOTAL RESECTION
Authors: Jonathan Knisely, Se Jung Chang, Sean H Kim, Arsalan Haghdel, Michelle Roytman, Gabriela Madera, Rajiv Magge, Benjamin Liechty, Philip Stieg, Susan Pannullo, Theodore Schwartz, Babacar Cisse, Andrew Brandmaier, Rupa Juthani, Evan Noch, Howard Fine, David Pisapia, Rohan Ramakrishna, Nicolas Karakatsanis, Joseph Osborne, Eaton Lin, Jana Ivanidze
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND MRI, the standard of care (SOC) for meningioma radiotherapy planning, lacks sensitivity for postoperative small volume disease and osseous or parenchymal invasion. BN003 (NCT03180268) randomizes patients with WHO-2 meningiomas and MRI-determined GTR to observation or 60 Gy IMRT to the resection bed. More sensitive and specific imaging biomarkers may improve clinical outcomes in meningioma by limiting unnecessary radiation of normal tissues and improving radiation targeting. [68Ga]-DOTATATE is a PET radiotracer targeting somatostatin receptor 2 (SSTR2), a highly sensitive and specific meningioma biomarker. We developed a dedicated DOTATATE brain PET/MRI protocol allowing meningioma differentiation from post-treatment change, using SUV analysis and Patlak modeling. Our prospective observational trial (NCT04081701) has imaged over 90 patients with meningioma. This IRB-approved study evaluated PFS in patients with WHO-2 tumors and postoperative GTR by [68Ga]-DOTATATE PET/MRI who were managed solely with active surveillance. We hypothesized that the PFS of patients with GTR by PET/MRI managed with active surveillance would be higher than for patients with MRI-determined GTR, using NRG-BN003’s observation arm (randomized trial comparing observation to fractionated radiotherapy) as a reference standard. METHODS 92 patients with SSTR2-positive brain neoplasms were enrolled between 9/2019 and 5/2022 and imaged according to our previously published protocol. 8 patients met inclusion criteria (WHO-2 meningioma &amp; postoperative PET/MR GTR) and were followed with SOC MRI. Kaplan-Meier survival analysis was performed. RESULTS 5/8 subjects (62.5%) were women; the mean age was 67 years. MRI follow-up data were available for a mean of 19.75 months (range: 7-38 months). One subject (12.5%) progressed at 21 months; the remainder remain progression-free. Kaplan-Meier analysis demonstrated 3-year PFS to be 80%, which is substantially higher than the reported 3-year PFS of 69% in the literature. CONCLUSIONS [68Ga]-DOTATATE PET can improve the specificity of imaging-based assessment of the extent of resection of WHO-2 meningiomas.
CSIG-22. THE MOLECULAR NETWORK OF CAMTA-1 IN GLIOMA CELLS
Authors: Lara Haeusser, Laurence Kuhlburger, Stefan Czemmel, Parameswari Govindarajan, Daniel Merk, Sven Nahnsen, Ghazaleh Tabatabai
Journal: Neuro-Oncology (2022)

Abstract Calmodulin-binding transcription activator 1 (CAMTA1) is a transcription factor located on chromosome 1p, and we have recently reported that CAMTA1 expression reduced neurosphere formation and tumor growth in nude mice, suggesting that CAMTA1 can function as tumor suppressor in experimental glioma. In the present study, we investigated the molecular network of CAMTA-1 in glioma cells. We established glioma cell lines with a doxycycline-inducible overexpression of CAMTA1. We performed a cap analysis of gene expression (CAGE) on these overexpressing cell lines to identify differentially regulated transcriptional start sites. We particularly focused on regulated target genes encoded on chromosome 19q. We identified an interaction of CAMTA1 overexpression with changes in the differential expression of Zink finger (ZNF) genes located on 19q. We will present novel data on a potential molecular interaction between chromosomes 1p and 19q.